Purpose.This
FOA issued by the Office of Strategic Coordination, National Institutes of
Health, solicits grant applications from institutions/ organizations that
propose to convert the International Knockout Mouse Consortium’s
knockout embryonic stem (ES) cell libraries (www.komp.org and www.eummcr.org),
into mice, perform quality control (QC) on the imported materials and
subsequent products, cooperatively send the mice to the successful grantees
under RFA-RM-10-011 for phenotyping, and
cryopreserve germplasm of those mice and send aliquots to the KOMP repository.
The overall objective of this FOA is to generate the resources needed by
NIH-funded Mouse Phenotyping Centers to produce functional information for each
protein coding gene in the mammalian genome as described in RFA-RM-10-011.

Mechanism of Support. This FOA will utilize
the U42 award mechanism and runs in parallel with two additional FOAs that solicits
applications under the U54 award
mechanism (RFA-RM-10-012, RFA-RM-10-011).

Funds Available and
Anticipated Number of Awards. Up to $12.4 million in total costs per year for periods
up to 5 years may be requested. It is anticipated that 1-3 awards will be made
contingent upon receiving scientifically meritorious proposals.

Budget and Project Period.The total project
period for an application submitted in response to this funding opportunity may
not exceed five years. Total costs are limited to $12,400,000 total costs per
year for a five-year period.

Eligible
Institutions/Organizations.Institutions/organizations listed in Section III, 1.A. are eligible to apply. Non-domestic
(non-U.S.) entities (Foreign Organizations) are not eligible to serve as
primary applicants for this FOA. However, foreign components may submit a
research project or subcontract within a domestic application, under this
FOA.

Eligible Project
Directors/Principal Investigators (PDs/PIs). Individuals with the
skills, knowledge, and resources necessary to carry out the proposed
research are invited to work with their institution/organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Number of PDs/PIs. More than
one PD/PI (i.e., multiple PDs/PIs), may be designated on the application.

Number of Applications.Applicants may
submit more than one application, provided they are scientifically
distinct.

Resubmissions. Resubmission applications are not
permitted in response to this FOA.

Renewals.Renewal applications
are not permitted in response to this FOA.

PURPOSE: The purpose of this
FOA, is to solicit applications for research projects to make maximum progress
toward the goal of converting the International Knockout Mouse Consortium
(IKMC) ES cell resource into mice, performing preliminary phenotyping, and
cryopreserving germplasm of those mice (which will be phenotyped by grantees
funded through an FOA being published in parallel). This is part of an overall
pilot effort aimed at developing a widely available resource of
well-characterized mutant mice that can be used by the scientific community to
elucidate functional information for each protein-coding gene in the mammalian
genome. Depending upon the success of this pilot, the program will be scaled up
during an additional 5 years to complete the phenotyping of a total of 8,500
knockout strains. The mouse is the ideal mammalian system in which to produce a
functional genomics resource because of the long history and depth of
understanding of mouse genetics, the sophistication of ES cell technology in
the mouse system, and the low cost of working with mice in comparison to other
mammals.

BACKGROUND: The mouse has
long been an important mammalian model system for the study of gene function in
human health and disease. Mouse mutants with phenotypes that mimic human traits
have served as critical research tools in understanding the genetics underlying
mammalian biology. Equally important, mouse mutants have been the tools used to
begin to understand gene function and pathways as the field has moved from gene
identification to mammalian functional genomics. Because of its importance to
human biology, mapping and sequencing the genome of mouse strain C57BL/6 was
carried out as part of the Human Genome Project. Another major genomic resource
for mouse research was developed by the Mammalian Gene Collection (MGC) project
(http://mgc.nci.nih.gov/),
which as of December 2009 included 27,285 full-ORF (open reading frame) cDNA
clones representing 17,701 individual mouse genes.

To complement the mouse
genome sequence and full-length cDNA collection, a defined genetic resource
that can be used to elucidate gene function is needed. To this end, a proposal
was made in the fall of 2003 to establish a focused, large-scale international
effort to produce a publicly available, comprehensive collection of mouse
knockout mutants, i.e., a library containing a null mutation in every gene in
the mouse genome (Austin, C.P., et al. Nature 36, 921-924 (2004)). The meeting
attendees recommended that this be accomplished in a phased production
approach, beginning with the construction of a resource of ES cells comprising
a comprehensive collection of null and conditional alleles. This would be
followed by the construction of mice from the ES cells and then phenotyping the
mice with an increasingly sophisticated set of tests. Tier 1, or basic
phenotyping, would be done on nearly all of the mice created by the project.
Tier 2, microarray and transcriptome based phenotyping, would be carried out on
a subset of these mice. Subsequent specialized phenotyping and further in depth
analyses on specific mice would then be pursued as part of individual research
programs.

There followed a number of
international efforts that further defined the proposed knockout mouse
resource. Following a March 2005 workshop which endorsed the concept (http://www.genome.gov/15014549),
the NIH launched the Knockout Mouse Program (KOMP) to generate knockout (null)
mutations in 8,500 genes in C57BL/6 knockout mice lines by deleting all or most
of the exons in target genes (Valenzuela, D.M., et al., Nature Biotechnology 6,
652-659 (2003)) or knockout-first conditional ready alleles (Testa, G., et al.,
Genesis 38, 151-158 (2004)). As of the end of June 2010, KOMP had produced
knockouts of about 5,500 genes and is on target to complete the goal of
producing 8,500 knockout mutant ES cell lines by the end of 2011. In parallel,
the European Conditional Mouse Mutagenesis Program (EuCOMM) and the North
American Conditional Mouse Mutagenesis Program (NorCOMM) are on track to
complete their goals of producing an additional 9,000 knockout mice by the end
of 2011. The three programs will thus produce a comprehensive resource of
mutant mouse ES cell lines. They have coordinated their efforts through the
formation of the International Knockout Mouse Consortium (IKMC).

As part of KOMP, the NIH
established a repository to archive, maintain, and distribute high quality ES
cell clones, as well as live mouse lines, frozen embryos and sperm, and vectors
(http://www.komp.org).
As part of its quality control procedures, KOMP is generating live mice from a
fraction of the ES cells as they are generated. The original goal was 500 and
current efforts are exceeding that goal. To date, 413 lines of mice have been
generated and, at current production rates, about 850 strains will be produced
by the end of 2011.

Thus, the first phase of the
proposed resource is on schedule to be completed by 2011, and attention has now
turned toward implementation of the second phase. Over the past year, there
have been a number of discussions, and planning a potential mouse phenotyping
effort has begun. The NIH held a KOMP Phenotyping Conference in Bethesda, MD in
October 2009, at which a group of researchers representing diverse scientific
backgrounds expressed their unanimous enthusiasm and support for a proposed
effort to conduct high-throughput and comprehensive phenotyping of the resource
being produced by the members of the IKMC (meeting report available at http://www.komp.org).
The meeting attendees were supportive of a proposed strategy to first convert
ES cells into mice at one or more high-throughput facilities that can also
efficiently conduct highly informative preliminary analyses (e.g., LacZ
expression, stage of embryonic lethality, fecundity), followed by performance
of a defined set of standard broad-based phenotype tests at KOMP phenotyping
facilities. The phenotyping data would be rapidly and freely released to the
public as they are generated, with the mice being archived for distribution to
the research community. The meeting participants stressed that any U.S.
phenotyping effort must be coordinated with comparable efforts elsewhere
(similar discussions and plans are being made in Europe, Canada, and Asia).The
standard phenotyping tests, analyses, and examinations that are included in the
resource effort should be chosen primarily on the basis of their reliability,
power, and likelihood to reveal disease and human clinical relevance. These
recommendations were highly similar to those that have come from other efforts
to solicit input from the US national research community.

The first large-scale
phenotyping effort was funded by the European Commission (EC) in 2008. The
European Mouse Disease Clinic (EUMODIC, http://www.eumodic.org/) program is
comprised of 4 mouse phenotyping centers, whose goals are to provide
phenotype information on 500 EUCOMM, NorCOMM and KOMP knockout mouse lines by
2011, using a common phenotyping protocol developed by the European Mouse
Phenotyping Resource of Standardized Screens (EMPReSS, http://empress.har.mrc.ac.uk/)
developed by the European Union Mouse Research for Public Health and Industrial
Applications (EUMORPHIA) Program. This data is made accessible through a
separately funded database, EUROPHENOME (http://www.europhenome.org/). It is
expected that the NIH will ask successful applicants to this RFA to coordinate
their efforts with the EUMODIC programs and the currently-forming International
Mouse Phenotyping Consortium (IMPC), to select knockout lines to be phenotyped,
harmonize phenotyping platforms, and make use of prior know-how and experience
(http://commonfund.nih.gov/KOMP2/ipmc-policies.asp).

RESEARCH OBJECTIVE: The KOMP
phenotyping program (KOMP2) will consist of several components. This
FOA solicits a mouse production capability of not less than 830 strains and up
to 2500 strains over five years. One companion FOA (RFA-RM-10-011) calls for applications to
propose a broad-based phenotyping program, and another companion FOA (RFA-RM-10-012) calls for proposals to
provide the bioinformatics support for the entire KOMP2 program.
Applicants may apply for more than one component by simultaneously applying to
more than one of the FOAs in coordinated applications, or by collaboration or
subcontracting approaches. For any approach, the proposed plans must be based
on realistic, documentable current capabilities and may include a ramp-up
period. The KOMP2 program is envisioned as a five year pilot, which
if successful, will be followed by 5 years of ramped up production with some
additional funds. Therefore, critical to the programs funded by all of
the FOAs listed above, will be plans to improve the technology and decrease
costs over the 5 years of the pilot phase.

ES Cell Handling: The KOMP2 program will involve one to three mouse production centers with a total
capability of converting 500 ES cell knockout lines per year to mouse strains,
for a total of 2500 over five years. Applicants should describe their past
and current abilities to handle hundreds of ES cell lines per year for
expansion, cryopreservation and archiving, as a demonstration of their ES cell
capabilities. The proposal should describe the steps that will be used to
handle the ES cells obtained from the IKMC, the projected throughput, the
production goals and explicit milestones, the characteristics and quality
expected of the mutant ES cell lines, the ES lines' potential to be transmitted
through the germline in mice, and all other pertinent factors. As mentioned
above, it would be preferable to demonstrate as much experience as possible in
the C57BL/6 background. However, since the technology to produce mice from ES
cells in a high throughput manner is more well-established for mouse strain
129, proposals from applicants that can demonstrate extensive experience with
ES cells of either the C57BL/6 or 129 backgrounds will be considered to be
responsive to the FOA.

Mouse Production from
Targeted ES cells: The applicant must present sufficiently detailed plans for
setting up and maintaining a production pipeline for the large-scale generation
of mouse lines from mutant ES cells obtained from the IKMC repositories (costs
detailed at www.komp.org and www.eummcr.org).
The specific ES cell lines to be turned into mice will be initially provided
and updated regularly during the course of the five year project by NIH.

Germplasm Cryopreservation:
The KOMP2 program includes the cryopreservation of mouse strains
after demonstration of successful germline transmission of targeted knockout
mutations. All mouse strains produced by this program will be made publicly
available as rapidly as possible, without a hold-back period, through
designated repositories (www.komp.org, or www.emmanet.org).

Neo Cassette and Critical
Exon Removal: The strategies used to generate the KOMP knockout mutations
lead to the retention of a Neo cassette in the genome of the derived ES cells.
It will be necessary to remove the Neo cassette from mice prior to phenotyping
to avoid effects of the heterologous promoter used to drive the Neo gene.

Mouse Breeding: Following
Cre excision, heterozygous null mice will be bred to determine if the
homozygous mice are viable and fertile. This plan should
include mating of homozygous male and female mice to proven breeders in order
to test fertility, as well as determination of embryonic or perinatal lethality
of the mutant allele being tested.

Lac Z expression profiling:
All IMKC mice contain a LacZ reporter inserted under the control of the
endogenous promoter of the mutated gene. Each application for a production
center must provide detailed plans to perform or outsource the analysis of
multi-tissues LacZ expression. The data and scanned images will be uploaded to
a mouse phenotyping database to be determined.

Plan for measuring embryonic
lethals: It is expected that a number of the knockout mutations will result in
embryonic lethality. Applications must propose a method to determine if death
occurs before or after embryonic day 12.

In addition to the above
strategy-specific issues, there are a number of production pipeline issues that
must be addressed by applications for all approaches:

Information Technology. The
applicant should discuss all pertinent informatics issues. These include, but
are not limited to, the informatics infrastructure of the production system,
such as the basic IT infrastructure/system administration, the laboratory
information management system, and the system for data handling and deposition.
It is vital that the production data and phenotypic data be provided in a
format that can be easily uploaded to external databases. It is anticipated
that the data uploads will occur on at least a bi-monthly basis, and include
sufficient tracking information to assure that project goals are being met.
This data set will include, at a minimum:

ES lines imported, ES lines
thawed, ES lines injected and/or aggregated, QC of 5% of ES lines, chimeras
born per line, % chimeras in each line, re-injected lines (with different
clones), chimeras breeding per line, germline results on each line, data on
breeding lines set up with Cre Deleter lines, offspring born in each line crossed
with Cre deleter lines, data confirming correct excision events with Cre
recombinase, mice bred to homozygosity, results of homozygosity breeding for
viability and fertility, mice in LacZ analysis, data from LacZ analysis,
materials shipped to phenotyping centers, and materials shipped to
repositories. Additional required data elements may be added, as needed. In all
cases, any necessary software development should be described in detail.

Technology development.
Incremental technology improvements always play an important role in increasing
the efficiency and decreasing the cost of high-throughput production processes,
and in the initial characterization of the production products. As noted above,
it is critical that the successful grantee improve the mouse production process
sufficiently so that continuation of the pilot program beyond the first five
years at a moderately higher funding level will be possible. Therefore
plans for technology development activities in the proposal are important to
the overall success of the program. The plans for technology improvement should
be well described, and the cost of any proposed technology development should
be justified in terms of the technology’s effect in reducing production
costs. The cost of such technology development will be included in the overall
production cost on a “per knockout” basis.

Quality control. The
applicant should discuss any means that will be taken to determine and ensure
the quality of, or otherwise validate, the resources that will be generated,
beyond those mentioned above. Examples of appropriate quality control
procedures include those for identification of the targeted allele,
confirmation of the knockout, demonstration that no undesired alterations have
occurred at the site of mutation, determination of the stability of the
integration and the copy number of the vector sequence , determination of the
ES cell germline potential, embryo or sperm cryopreservation, and testing the
pathogen status of all biological reagents. The applicant should briefly
discuss their proposed animal husbandry conditions, and their experience in
producing standardized mice to be phenotyped. Evidence of the
effectiveness of the proposed quality control programs should be included.

Costs per gene knockout
strain produced. The applicant should describe plans for determining and
reducing the cost of generating knockout mice. All proposed costs and projected
cost reductions should be given in terms of the total costs, i.e. the fully
loaded costs (including overhead). These costs will be reported by the
applicant on a quarterly basis and tracked by the NIH.

In summary, applicants for
awards under this FOA should:

discuss
the approaches or strategies to be used for the production of knockout mice,
including the applicant's current efforts (throughput and cost) in this area
and how those efforts will ramp to achieve the proposed goals;

present
explicit production milestones and timelines when describing production goals;

This funding opportunity
will use a cooperative agreement award mechanism. In
the cooperative agreement mechanism, the Project Director/Principal Investigator
(PD/PI) retains the primary responsibility and dominant role for planning,
directing, and executing the proposed project, with NIH staff being
substantially involved as a partner with the Principal Investigator, as
described under the Section VI. 2. Administrative
Requirements, "Cooperative Agreement Terms and Conditions of
Award". The KOMP2 project may be
continued for an additional five year period, depending on the results of a
program review in the 3rd or 4th year of the initial project, but new FOAs will
be issued rather than accept applications for a renewal of this FOA.

2. Funds Available

Up to $62 million in total costs over 5
years is to be awarded through this FOA;

It is anticipated that 1-3 awards will
be made;

Therefore, depending on the number of
awards, the expected total cost amount for individual awards will be $4.1
– 12.4 million per year;

Because the nature
and scope of the proposed research will vary from application to application,
it is anticipated that the size and duration of each award will also vary.
Although the financial plans of the IC(s) provide support for this program,
awards pursuant to this funding opportunity are contingent upon the
availability of funds and the receipt of a sufficient number of meritorious
applications.

Facilities and
administrative costs requested by consortium participants are not included in
the direct cost limitation, see NOT-OD-05-004.

NIH
grants policies as described in the NIH Grants Policy
Statement will apply to the applications submitted and awards made in
response to this FOA.

Foreign
institutions are not eligible to apply in response to this FOA; however,
subcontractual
arrangements with foreign institutions are allowed.

1.B.
Eligible Individuals

Any
individualwith the skills, knowledge, and resources necessary to
carry out the proposed research as the PD/PI is invited to work with his/her
institution to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH program support.

More than one PD/PI, or
multiple PDs/PIs, may be designated on the application for projects that
require a “team science” approach and therefore clearly do not fit
the single-PD/PI model. Additional
information on the implementation plans, policies and procedures to formally
allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi.All PDs/PIs must be registered in the NIH eRA
Commons prior to the submission of the application (see http://grants.nih.gov/grants/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to
apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility
of the investigators and applicant organizations, and should be determined by
the scientific goals of the project. Applications for grants with multiple
PDs/PIs will require additional information, as outlined in the instructions
below. When considering multiple PDs/PIs, please be aware that the structure
and governance of the PD/PI leadership team as well as the knowledge, skills
and experience of the individual PDs/PIs will be factored into the assessment
of the overall scientific merit of the application. Multiple PDs/PIs on a
project share the authority and responsibility for leading and directing the
project, intellectually and logistically. Each PD/PI is responsible and
accountable to the grantee organization, or, as appropriate, to a collaborating
organization, for the proper conduct of the project or program, including the
submission of required reports. For further information on multiple PDs/PIs,
please seehttp://grants.nih.gov/grants/multi_pi.

Principal Investigator (P.I.) Effort. The
effective management of a production project requires a significant commitment
by the P.I. The P.I. of a large-scale project funded under this FOA is expected
to devote at least 2.4 (CY) person months to the project. Additionally, it will
be helpful for the applicant to describe how he/she envisions managing the
proposed project, and how that management will support achievement of the
proposed goals and milestones. Useful elements of this description include the
organization of the proposed production effort, its management structure,
including integration of the separate components to form an efficient pipeline,
key personnel, section leaders, and reporting relationships. Recruitment and
training of personnel may also be discussed. The plan should also describe how
the various components of the proposed production effort will be integrated,
and how collaborations or subcontracts, if proposed, will be managed. It would
be useful to discuss coordination of the awardee's activities with those of
other international efforts to produce mouse knockouts.

Applications must have a D&B Data Universal
Numbering System (DUNS) number as the universal identifier when applying for
Federal grants or cooperative agreements. The D&B number can be obtained by
calling (866) 705-5711 or through the web site at http://www.dnb.com/us/.
The D&B number should be entered on line 11 of the face page of the PHS 398
form.

The title and
number of this funding opportunity must be typed in item (box) 2 only of the
face page of the application form and the YES box must be checked.

Foreign
Organizations (Non-domestic
(non-U.S.) Entity)

Non-domestic
(non-U.S.) entities (Foreign Organizations) are not eligible to serve as
primary applicants for this FOA. However, foreign components may submit a
research project or subcontract within a domestic application, under this FOA.

Every effort should be made to comply with the
format specifications, which are based upon a standard U.S. paper size of
8.5” x 11” within each PDF.

Funds for up to 8% Facilities and Administrative
(F&A) costs (excluding equipment) may be requested. SeeNOT-OD-01-028, March 29, 2001.

Organizations must comply with Federal/NIH
policies on human subjects, animals, and biohazards.

Organizations must comply with Federal/NIH
biosafety and biosecurity regulations. See Section VI.2.,
“Administrative and National Policy Requirements”

Proposed research should provide special
opportunities for furthering research programs through the use of unusual
talent, resources, populations, or environmental conditions in other countries
that are not readily available in the United States or that augment existing
U.S. resources.

Applications
with Multiple PDs/PIs

When multiple PD/PIs are
proposed, use the Face Page-Continued page to provide items 3a – 3h for
all PD/PIs. NIH requires one PD/PI be designated as the “contact
PD/PI” for all communications between the PD/PIs and the agency. The
contact PD/PI must meet all eligibility requirements for PD/PI status in the
same way as other PD/PIs, but has no special roles or responsibilities within
the project team beyond those mentioned above. The contact PD/PI may be changed
during the project period. The contact PD/PI should be listed in block 3 of
Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page
1-Continued. When inserting the name of the PD/PI in the header of each
application page, use the name of the “Contact PD/PI, et. al.” The
contact PD/PI must be from the applicant organization if PD/PIs are from more
than one institution.

All individuals designated
as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI
role in that system (other roles such as SO or IAR will not give the PD/PI the
appropriate access to the application records). Each PD/PI must include their
respective eRA Commons ID in the eRA Commons User Name field.

Multiple
PD/PI Leadership Plan: For applications designating multiple PDs/PIs, the
section of the Research Plan entitled, “Multiple PD/PI Leadership
Plan”, must be included. A rationale for choosing a multiple PD/PI
approach should be described. The governance and organizational structure of
the leadership team and the research project should be described, and should
include communication plans, process for making decisions on scientific
direction, and procedures for resolving conflicts. The roles and
administrative, technical, and scientific responsibilities for the project or
program should be delineated for the PDs/PIs and other collaborators.

If
budget allocation is planned, the distribution of resources to specific
components of the project or the individual PDs/PIs should be delineated in the
Leadership Plan. In the event of an award, the requested allocations may be
reflected in a footnote on the Notice of Award (NoA).

Prospective
applicants are asked to submit a letter of intent that includes the following
information:

Descriptive title of proposed research

Name, address, and telephone number of
the Principal Investigator

Names of other key personnel

Participating institutions

Number and title of this funding
opportunity

Although a letter of
intent is not required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows IC staff to
estimate the potential review workload and plan the review.

Applications
must be prepared using the forms found in the PHS 398 instructions for
preparing a research grant application. Submit a signed, typewritten original
of the application, including the checklist, and three signed photocopies in one package to:

Applications must be received on or before the
application receipt date described above (Section
IV.3.A.). If an application is received after that date, the application
may be delayed in the review process or not reviewed. Upon receipt,
applications will be evaluated for completeness by the CSR and for
responsiveness by the reviewing Institute. Incomplete and/or non-responsive
applications will not be reviewed.

The NIH will not
accept any application in response to this funding opportunity that is
essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application. However, when a previously
unfunded application, originally submitted as an investigator-initiated
application, is to be submitted in response to a funding opportunity, it is to
be prepared as a NEW application. That is, the application for the funding
opportunity must not include an Introduction describing the changes and
improvements made, and the text must not be marked to indicate the changes from
the previous unfunded version of the application.

All NIH awards
are subject to the terms and conditions, cost principles, and other
considerations described in the NIH Grants Policy Statement. The Grants Policy
Statement can be found at NIH Grants
Policy Statement.

Pre-award costs
are allowable. A grantee may, at its own risk and without NIH prior approval,
incur obligations and expenditures to cover costs up to 90 days before the
beginning date of the initial budget period of a new award if such costs: 1)
are necessary to conduct the project, and 2) would be allowable under the
grant, if awarded, without NIH prior approval. If specific expenditures would
otherwise require prior approval, the grantee must obtain NIH approval before
incurring the cost. NIH prior approval is required for any costs to be incurred
more than 90 days before the beginning date of the initial budget period of a
new award.

The incurrence
of pre-award costs in anticipation of a competing or non-competing award
imposes no obligation on NIH either to make the award or to increase the amount
of the approved budget if an award is made for less than the amount anticipated
and is inadequate to cover the pre-award costs incurred. NIH expects the
grantee to be fully aware that pre-award costs result in borrowing against
future support and that such borrowing must not impair the grantee's ability to
accomplish the project objectives in the approved time frame or in any way
adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Requirements

A Special Guidance for
Applicants.

The NHGRI and NCRR (two of
the NIH Institutes supporting this FOA) have conducted several competitions for
large-scale projects and have noted that there are specific information items
and presentation formats that the reviewers have found to be critical for their
ability to assess proposals for such efforts effectively. The following
guidance summarizes that experience in the form of a format that the applicant
may use to provide that information. If there is additional information, not
addressed in this Guidance, that the applicant wishes to present, s/he is
encouraged to provide it in a concise form, in addition to the information
requested here. Following are specific instructions that may be used for
writing the Report of Track Record and the Research Proposal for the approaches
called for in this RFA.

6. Guidance for applications
proposing mouse production:

6.I. Report of track record.
The report of track record section should adequately describe the applicant's
past experience in production of mice from ES cells; brief, concise summaries
are encouraged. The report of track record should represent the applicant's
past accomplishments, rather than future plans and should include the
following:

6.I.1. Production and
distribution of knockout mice. The applicant should describe past and current
efforts to construct and distribute knockout mice from ES cells. The
description should include discussion of the throughput rate, quality, and
cost, and should include, but not be limited to, the following information:

a. Throughput and quality:

i. The number of mice made
in the most recent six months of activity, either by blastocyst or morula
injection or by aggregation. Describe the process(es) used, including tasks
performed and individuals' efforts. For example, was the process organized by
task or did each individual perform multiple steps?

ii. Any use of probes for
assessing whether or not a knockout was transmitted through the germline. Was
the screening PCR-based? What was the monthly success rate of germline
transmission during the most recent six month period?

iii. The total current total
monthly production in the applicant's laboratory or center. This number should
be based on an average of at least the last six months of mouse production and
should include the number of attempted injections/aggregations, the number of
successful injections/aggregations, and the number of FTE or equivalents
needed. What were the main reasons for any failures?

iv. Any other metrics that
the applicant has found to be useful in evaluating and managing the production
of knockout mice from ES cells.

v. The total number of
knockout mice distributed to other institutions in the past six months.

6.I.2. Mutant mouse
cryopreservation. The applicant should describe efforts over at least the most
recent six months of activity to cryopreserve mouse germplasm. The strain
background of the mice (129, C57BL/6, or other) should be clearly identified.
The discussion should address the steps of breeding and crypopreservation,
quality control, and re-animation. The applicant should describe the rate of
throughput, quality (e.g., re-animation rate), and cost, and should include,
but not be limited to, the following:

a. Throughput and quality:

i. The number of strains
cryopreserved per month in the most recent six months of activity;

ii. The form of germplasm
cryopreserved, i.e., embryos or sperm;

iii. Steps taken to ensure
that cryopreservation was successful. What is the current success rate and how
has it changed over the course of the past year?

iv. Any other internal
metrics that the applicant has found to be useful in evaluating and managing
the production of cryopreserved germplasm.

6.I.3. Technology
Development. The applicant should address any experience that s/he has had in
developing and improving technology for mouse production, distribution and
cryopreservation. The discussion should describe, in quantitative terms, the
effect that such technology improvements have had in process improvement and
decreased production costs.

6.I.4. Prior experience in
attaining milestones. The applicant should discuss his/her experience in
defining and meeting useful milestones and budgets in a biological production
effort.

6.II. The Research Proposal.
This section comprises the applicant's description for a production project to
generate strains of live mice from knockout ES cells (830 - 2500 over five
years), characterize, and cryopreserve them. The organization suggested below
for this section of the application is based on the NIH staff's current
understanding of the steps in these processes. The applicant is free to propose
an alternative organization or strategy but, in so doing, must address all of
the issues raised below.

6.II.1. Knockout mouse
production and distribution. The applicant should present a clear plan,
including concrete milestones, for (1) achieving production of a sufficient
number of chimeric founder mice in order to characterize and cryopreserve 830 -
2500 knockout mouse strains over five years, and (2) increasing the efficiency
of chimeric mouse production. The techniques employed
are expected to include, but are not limited to, ES microinjection (either
morula or blastocysts) and aggregation chimeras, and are at the discretion of
the applicant. The application should present both a cost analysis for generating
lines with the techniques employed and a detailed assessment of past and
current success rates. The applicant’s projected production rates and
costs (including the purchase of mutant ES cell lines from the repositories)
should be justified in detail. Information on how the applicant has improved
the process and reduced costs in the past and plans for future improvements
should be included.All phases of the production process must be addressed, as
well as:

i. the overall projected
throughput and how it will be attained;

ii. potential bottlenecks or
other problems that can be anticipated, as well as proposed solutions;

iii. timelines and
quantitative milestones where appropriate;

iv. QC
method(s) for screening to confirm the correct genotype of ES cell lines and
mice

Neo Cassette and Critical Exon Removal. The
applicant should describe in sufficient detail the Cre lines and their genetic
backgrounds that will be used to remove the expression cassette. Alternatively,
the applicant may propose and justify a plan to remove the Neo selection
cassette by transfection of ES cells with a Cre-expressing plasmid. A detailed
molecular analysis should be described to ensure the integrity of the alleles
following Cre deletion. Cryopreservation of germplasm, but not necessarily
embryos, should also be performed.

i. the overall projected
throughput and how it will be attained;

ii. potential bottlenecks or
other problems that can be anticipated, as well as proposed solutions;

iii. timelines and
quantitative milestones where appropriate;

iv. QC
method(s) for screening to confirm the correct genotype of ES cell lines or
mice

6.II.2. Fecundity testing.
The applicant should provide a clear plan to test the fecundity of the derived
knockout mouse strains. The applicant should describe breeding
schemes, number of offspring that will need to be observed, and his/her ability
to perform (or outsource) genotyping of at least 250 mutant mouse lines per
year. The applicant should also describe the available space that will be used
for the breeding of the necessary mouse lines and the duration for which this
space will be available for the project funded under this FOA. The applicant
should describe an efficient plan to export either live mice or germplasm to
Phenotyping Centers funded under the companion FOA (RFA-RM-10-011). In cases where the animals
die before weaning or are deemed too sick for phenotyping, the applicant should
describe a plan to provide heterozygous mice or germplasm to the phenotyping
centers.It is expected that a number of the knockout
mutations will result in embryonic lethality. Applications must propose a
method to determine if death occurs before or after embryonic day 12. All
phases of the production process must be addressed, as well as:

i. the overall projected
throughput and how it will be attained;

ii. potential bottlenecks or
other problems that can be anticipated, as well as proposed solutions;

iii. timelines and quantitative
milestones where appropriate;

6.II.3. LacZ staining. The
applicant should provide a clear plan to collect and section tissues from adult
male and female mice and then stain sections to detect LacZ expression. The
rationale for tissue selection should be presented. In addition the applicant
should discuss a plan to perform wholemount staining of embryos. Rationale
should be presented for the age of the embryo to be observed and for the
particular techniques that will be employed. The plan to image the
stained sections and wholemounts, annotate, and organize the data should be
presented. All phases of the production process must be addressed, as well as:

i. the overall projected
throughput and how it will be attained;

ii. potential bottlenecks or
other problems that can be anticipated, as well as proposed solutions;

iii. timelines and
quantitative milestones where appropriate;

6.II.4. Cryopreservation of
mouse germplasm. The applicant should present a clear plan, including concrete
milestones, for (1) cryopreservation of germplasm for the 830 - 2500 mouse
strains produced, and (2) increasing the efficiency of production over the
five-year time frame of this initiative. All phases of the production pipeline
(natural matings or in vitro fertilization, sperm harvesting, freezing) and
quality control steps (reanimation, pathogen testing) should be addressed, as
well as:

i. the overall projected
throughput and how it will be attained;

ii. potential bottlenecks or
other problems that can be anticipated, as well as proposed solutions;

iii. timelines and
quantitative milestones where appropriate;

6.II.5. Informatics. All
production data and materials should be linked to the gene as the reference
point. The informatics issues and requirements associated with mutant mouse
production should be discussed in a manner such that all of the data will be
integrated and linked to information on the gene of interest. It is anticipated
that developing the gene list to be produced will be an ongoing iterative process
done in conjunction with NIH staff, other participants in the KOMP phenotyping
program, and the Panel of Scientific Consultants (see below). The successful
grantee will be expected to transfer all relevant data to a database to be
determined. The applicant should propose how a plan to transfer data will be
developed and suggest elements of that plan if possible. This data exchange
format should contain elements to describe data related to all steps in the
process of generating knockout mutants and be an explicitly defined, machine
readable format.

6.II.6. Technology
development. The Research Plan should include a separate section describing
plans for technology development efforts to improve the efficiency of the
production pipeline for making mutant mice during the proposed project through
innovation rather then simple improvements in process control.

6.III. Budget Request. The
budget requested must be described clearly and be well justified. Applicants
should submit the Detailed Budget for the Initial Budget Period (page 4 of
PHS-398) and the Budget for Entire Proposed Period of Support (page 5 of
PHS-398)

Awardees must agree to the
"Cooperative Agreement Terms and Conditions of Award" in Section
VI.2.A "Award Administration Information".

PHS398 Research Plan Sections

All
application instructions outlined in the PHS398 Application Instructions are to
be followed, with the following additional requirements:

Research
Strategy, including tables, graphs, figures, diagrams, and charts is limited to 30 pages.

Do not use
the Appendix to circumvent the page limitations. An application that does
not observe the required page limitations may be delayed in the review process.

Resource Sharing
Plan(s)

NIH considers the sharing of unique research
resources developed through NIH-sponsored research an important means to
enhance the value of, and advance research. When resources have been developed
with NIH funds and the associated research findings published or provided to
NIH, it is important that they be made readily available for research purposes
to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing,
this should be explained in Resource Sharing section of the application.
See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(b) Sharing Model Organisms:
Regardless of the amount requested, all applications where the development of
model organisms is anticipated are expectedto include a
description of a specific plan for sharing and distributing unique model
organisms and related resources, or state appropriate reasons why such sharing
is restricted or not possible. See Sharing
Model Organisms Policy, and NIH
Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a
genome-wide association study are expected to provide a plan for
submission of GWAS data to the NIH-designatedGWAS data
repository, or provide an appropriate explanation why submission to the
repository is not possible. A genome-wide association study is defined as
any study of genetic variation across the entire genome that is designed to
identify genetic associations with observable traits (such as blood pressure or
weight) or the presence or absence of a disease or condition. For further
information see Policy for Sharing of Data Obtained in NIH Supported or
Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

All applications are
expected to include a plan for sharing research data. The standard NIH data
sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All
investigators responding to this funding opportunity should include a
description of how final research data will be shared, or explain why data
sharing is not possible. However, rapid release of the data would be of benefit
to the scientific user community because of the scope of this community
resource project as described in this FOA and because of the national and
scientific investment that the NIH will make in KOMP2. Accordingly,
applicants should not feel constrained by the standard approach to data sharing
but should display and promote innovative methods for achieving the maximum use
of the KOMP2 resource.

Data release. Applicants
should be familiar with the NIH statements regarding sharing of resources
developed with Federal funds
(http://grants.nih.gov/grants/intell-property_64FR72090.pdf). In the case of
phenotypic data, plans for the dissemination and access of the data to a centralized
database is needed in line with the aims of the RFA. With regard to the present
solicitation, NHGRI and the other participating Institutes have identified the
goal of the KOMP2 as the production of a “community
materials” as described in the proceedings of the Meeting on Sharing Data
from Large-Scale Biological Research Projects (http://www.wellcome.ac.uk/doc_wtd003208.html).
Therefore, responses to this RFA should propose a specific and comprehensive
plan for the rapid release of data resulting from the knockout mouse production
and phenotyping effort to the appropriate databases. None of the funds of this
project are intended to support the creation of a publically accessible database
for each phenotyping center, as it is envisioned that a single separately
funded database will provide public access to all phenotyping data. The quality
of this plan will be an important criterion in the award of the cooperative,
and an appropriate plan for release of data and materials will be made a
condition of the awards made as a result of this RFA.

In presenting the data
release plan, the release of data to the project's public website should be
discussed and should include, but is not limited to: information as to the
genes that have been assigned to the project, when the effort to study the mice
is scheduled to begin or actually began, data that confirm a knockout mouse has
been successfully made, date that data were collected and shipped to a central
phenotyping database, and other pertinent data.

Additionally, the
applicant's data release plan should address how software or technology
improvements developed under this funding will be publicly released. It is
highly likely that software solutions and LIMS system development would benefit
the other IMPC phenotyping centers as well as other investigators.

The release plans are
expected to fully address how the end users of the mice, embryos, data, and
other materials generated by the funded activity, in both the public and
private sectors, will be fully enabled to share and use the materials,
consistent with achieving the goals of this project.

The reviewers will assess
the reasonableness of the data sharing plan or the rationale for not sharing research
data. Program staff of the funding organization, when making recommendations
about funding applications, will consider the adequacy of the resources sharing
plan and any related data sharing plans. Section I. “Research
Objectives” contains a section entitled “Data and Materials
Release” that addresses the issues that can be used in a data-sharing
plan for a KOMP2 component.

Sharing Research Resources

NIH policy expects that
grant awardee recipients make unique research resources readily available for
research purposes to qualified individuals within the scientific community
after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm
- _Toc54600131). Investigators responding to this funding
opportunity should include a plan for sharing research resources addressing how
unique research resources will be shared or explain why sharing is not
possible. However, as indicated in the previous section with respect to the
data sharing plan, applicants should not feel constrained to propose a standard
plan for sharing materials, given the scope of KOMP2 as defined by
the FOA and the NIH's investment in this project. Widespread dissemination and
access to the materials generated through this program to the public and
private research sectors are an aim of this FOA and will require innovative
methods for achieving the maximum use of the resource to be produced under this
project.

Program staff of the funding
organization, when making recommendations about funding applications, will
consider the adequacy of the resources sharing plan and any related data
sharing plans. The effectiveness of the resource sharing will be evaluated as
part of the administrative review of each non-competing Grant Progress Report
(PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm).
See Section VI.3. Reporting.

Material Transfer. A uniform
MTA such as the Simple Letter Agreement (SLA), Material Transfer Agreement for
the Transfer of Organisms (MTA-TO) will be used for all repositories which
receive resources made by this effort to ensure that the resources made by this
initiative are available in a manner consistent with the goals of this RFA and
with no additional reach-through rights to inventions/discoveries made by the
end users. Although NIH Policy strongly discourages the patenting of research
resources, applicants are free to patent their discoveries so long as the ES
cells, embryos, mice, and data are made available for research purposes in a
manner consistent with the NIH Data Sharing Policy, other NIh sharing policies
(see http://sharing.nih.gov), and the goals of this FOA. Applicants will not be
separate distribution centers or develop public websites, unless agreed to by
the current repositories and the NIH Program Officer.

Authorization and Consent

(a) The Government authorizes and consents to all use and manufacture of
any invention described in and covered by a United States patent in the
performance of this Cooperative Agreement at all tiers.

Notice and Assistance Regarding Patent and Copyright Infringement.

(a) The Grantee shall report to the Program Director, promptly and in
reasonable written detail, each notice or claim of patent or copyright
infringement based on the performance of this Cooperative Agreement of which
the Grantee has knowledge.

(b) In the event of any claim or suit against the Government on account
of any alleged patent or copyright infringement arising out of the performance
of this Cooperative Agreement or out of the use of any supplies furnished or
work or services performed under this Cooperative Agreement, the Grantee shall
furnish to the Government, when requested by the Program Director, all evidence
and information in possession of the Grantee pertaining to such suit or claim.
Such evidence and information shall be furnished at the expense of the
Government except where the Grantee has agreed to indemnify the Government.

(c) The Grantee agrees to include, and require inclusion of, this clause
in all sub-awards and subcontracts at any tier for supplies or services
(including construction and architect-engineer sub-awards and subcontracts and
those for material, supplies, models, samples, or design or testing
services).

Awardees must agree to the "Cooperative Agreement Terms and
Conditions of Award" in Section
VI.2.A.

Section
V. Application Review Information

1. Criteria

Only the review
criteria described below will be considered in the review process.

2. Review and Selection Process

Review Process

Applications
that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group
convened by NHGRI and in accordance with NIH
peer review procedures (http://grants1.nih.gov/grants/peer/), using
the review criteria stated below.

As part of the scientific peer
review, all applications will:

Undergo
a selection process in which only those applications deemed to have the
highest scientific and technical merit, generally the top half of
applications under review, will be discussed and assigned an
impact/priority score.

Receive
a written critique.

Receive
a second level of review by the National Advisory Research Resources
Council.

The mission
of the NIH is to support science in pursuit of knowledge about the biology and
behavior of living systems and to apply that knowledge to extend healthy life
and reduce the burdens of illness and disability. As part of this
mission, applications submitted to the NIH for grants or cooperative agreements
to support biomedical and behavioral research are evaluated for scientific and
technical merit through the NIH peer review system.

Overall Impact

Reviewers
will provide an overall impact/priority score to reflect their assessment of
the likelihood for the project to exert a sustained, powerful influence on the
research field(s) involved, in consideration of the following five scored
review criteria, and additional review criteria (as applicable for the project
proposed).

Scored Review Criteria

Reviewers
will consider each of the five review criteria below in the determination of
scientific and technical merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature
is not innovative may be essential to advance a field.

Significance. Does the project address an important problem or a critical
barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change
the concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited
to the project? If Early Stage Investigators or New Investigators, or in
the early stages of independent careers, do they have appropriate experience
and training? If established, have they demonstrated an ongoing record of
accomplishments that have advanced their field(s)? If the project is
collaborative or multi-PD/PI, do the investigators have complementary and
integrated expertise; are their leadership approach, governance and
organizational structure appropriate for the project?

Innovation. Does the application challenge and seek
to shift current research or clinical practice paradigms by utilizing novel
theoretical concepts, approaches or methodologies, instrumentation, or
interventions? Are the concepts, approaches or methodologies,
instrumentation, or interventions novel to one field of research or novel in a
broad sense? Is a refinement, improvement, or new application of
theoretical concepts, approaches or methodologies, instrumentation, or
interventions proposed?

Approach. Are the overall strategy, methodology, and analyses well-reasoned
and appropriate to accomplish the specific aims of the project? Are
potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will
the strategy establish feasibility and will particularly risky aspects be
managed?
If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment. Will the scientific environment in which the work will be done contribute
to the probability of success? Are the institutional support, equipment
and other physical resources available to the investigators adequate for the
project proposed? Will the project benefit from unique features of the
scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable
for the project proposed, reviewers will consider the following additional items in the determination of scientific and
technical merit, but will not give separate scores for these items.

The
likelihood that the proposed center can produce a high-quality set of mouse
mutants, and cryopreserve mouse embryos and/or sperm.

The
quality of the plans for technology development improvement and identifying and
solving critical integration problems.

The
quality of the plans for bioinformatics, including infrastructure and
laboratory information management systems.

The
quality of the plans for release of data and materials, including evidence that
the systems are in place to support data release.

The
quality of the plans for release or distribution of other resources, software,
or technologies developed under this award, including evidence that the systems
are in place to support data release.

The
quality of the plans to coordinate efforts with other mouse mutagenesis
projects in the U.S. and abroad, and with appropriate subcontractors or
collaborators that may be needed.

The
track record of the Principal Investigator and other key personnel in producing
and disseminating mouse knockouts.

The
reasonableness of the milestones, timelines, and goals proposed for the
research project.

Protections
for Human Subjects. For research that
involves human subjects but does not involve one of the six categories of
research that are exempt under 45 CFR Part 46, the committee will evaluate the
justification for involvement of human subjects and the proposed protections
from research risk relating to their participation according to the following
five review criteria: 1) risk to subjects, 2) adequacy of protection against
risks, 3) potential benefits to the subjects and others, 4) importance of the
knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research
that involves human subjects and meets the criteria for one or more of
the six categories of research that are exempt under 45 CFR Part 46, the
committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials.

Inclusion
of Women, Minorities, and Children. When
the proposed project involves clinical research, the committee will evaluate
the proposed plans for inclusion of minorities and members of both genders, as
well as the inclusion of children.

Vertebrate
Animals. The committee will evaluate the
involvement of live vertebrate animals as part of the scientific assessment
according to the following five points: 1) proposed use of the animals, and
species, strains, ages, sex, and numbers to be used; 2) justifications for the
use of animals and for the appropriateness of the species and numbers proposed;
3) adequacy of veterinary care; 4) procedures for limiting discomfort,
distress, pain and injury to that which is unavoidable in the conduct of
scientifically sound research including the use of analgesic, anesthetic, and
tranquilizing drugs and/or comfortable restraining devices; and 5) methods of
euthanasia and reason for selection if not consistent with the AVMA Guidelines
on Euthanasia.For
additional information, see http://grants.nih.gov/grants/olaw/VASchecklist.pdf.

Biohazards. Reviewers will assess whether materials or procedures proposed are
potentially hazardous to research personnel and/or the environment, and if
needed, determine whether adequate protection is proposed.

Resubmission Applications. Resubmissions are not applicable to this FOA.

Renewal
Applications. Renewals are not applicable to this
FOA.

Revision
Applications. Revisions are not applicable to this
FOA.

Additional Review Considerations

As applicable
for the project proposed, reviewers will address each of the following items,
but will not give scores for these items and should not consider them in
providing an overall impact/priority score.

Applications
from Foreign Organizations. Foreign institutions are not eligible to apply in
response to this FOA; however, subcontractual arrangements with foreign
institutions are allowed.

Select
Agents Research. Reviewers will assess the information provided in this section of the application, including
1) the Select Agent(s) to be used in the proposed research, 2) the registration
status of all entities where Select Agent(s) will be used, 3) the procedures
that will be used to monitor possession use and transfer of Select Agent(s),
and 4) plans for appropriate biosafety, biocontainment, and security of the
Select Agent(s).

A
formal notification in the form of a Notice of Award (NoA) will be
provided to the applicant organization. The NoA signed by the grants management
officer is the authorizing document. Once all administrative and programmatic
issues have been resolved, the NoA will be generated via email notification
from the awarding component to the grantee business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the extent
considered allowable pre-award costs. See Also Section
IV.5. Funding Restrictions.

The
following Terms and Conditions will be incorporated into the award statement
and will be provided to the Principal Investigator as well as to the
appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms
and Conditions of Award

The following special
terms of award are in addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS grant administration regulations at 45 CFR Parts
74 and 92 (Part 92 is applicable when State and local Governments are eligible
to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and
funding instrument used for this program will be the cooperative agreement an
"assistance" mechanism (rather than an "acquisition"
mechanism), in which substantial NIH programmatic involvement with the awardees
is anticipated during the performance of the activities. Under the cooperative
agreement, the NIH purpose is to support and stimulate the recipients'
activities by involvement in and otherwise working jointly with the award
recipients in a partnership role; it is not to assume direction, prime
responsibility, or a dominant role in the activities. Consistent with this
concept, the dominant role and prime responsibility resides with the awardees
for the project as a whole, although specific tasks and activities may be
shared among the awardees and the NIH as defined below.

2.
A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary
responsibility fordefining the details for the gene knockout production project
within the guidelines of RFA-RM-10-013 and for performing the scientific
activities. The P.I. will agree to collaboration with the other members of the
KOMP2 Research Network and to accept close coordination,
cooperation, and participation of NIH staff and advisors in those aspects of
scientific and technical management of the project as described under 2.A.2.
NIH Responsibilities.

Accept
and participate in the cooperative nature of the KOMP2 Research
Network;

Serve,
along with the P.I. of each of the other funded KOMP2 Research
Network awards, on the Steering Committee for the KOMP2 Research
Network; the P.I. will have one vote on the Steering Committee;

Provide
goals for throughput, quality, and cost to the NCRR and NHGRI as requested
(usually at the outset of the award and in monthly progress reports to the
Steering Committee, but also at other times as requested by NCRR, and NHGRI
program staff);

Ensure
that the products of the production effort meet or exceed the quality standards
and costs agreed upon at the time of award;

Submit
data for quality assessment in any manner specified by the Steering Committee
or the Panel of Scientific Consultants;

Submit
periodic progress reports in a standard format, as agreed upon by the Steering
Committee and the Panel of Scientific Consultants;

Ensure
that the data (sequence and quality assessment data and probes) are deposited
in the appropriate public databases (e.g., the grantee to be funded by
RFA-RM-10-012, as specified by NHGRI program staff), that resources developed
as part of this project are made publicly available through an NIH-designated
repository according to NIH policies;

Adhere
to the general NIH policies regarding sharing resources, data release, and
resource sharing, as well as the specific data and resource-sharing policies
proposed in the application, as modified by any negotiation prior to award or
that might be established by the Steering Committee during the course of this
activity;

Accept
and implement any other common policies, guidelines and procedures that are
developed and approved for the KOMP2 by the Steering Committee and
the Panel of Scientific Consultants;

Coordinate
and collaborate with other U.S. and international groups producing mouse
knockout mutants as a community resource;

Inform
the NCRR and NHGRI Program Directors of all major interactions with members of
the Steering Committee;

Attend
a yearly Steering Committee meeting with the Panel of Scientific Consultants.

Awardees
will retain custody of and have primary rights to the data and software
developed under these awards, subject to Government rights of access consistent
with current HHS, PHS, and NIH policies.

2.
A.2. NIH Responsibilities

An NIH Project
Scientist will have substantial programmatic involvement that is above and beyond
the normal stewardship role in awards, as described below.For the KOMP2 Research Network, a Project
Scientist will be appointed from each of the Institutes that is responsible for
the participating cooperative agreements, that is, NCRR and NHGRI.

For RFA-RM-10-013 (this
RFA), the NCRR Project Scientist will have substantial scientific/programmatic
involvement during the conduct of this activity through technical assistance,
advice and coordination. However, the role of the NCRR Project Scientist will
be to facilitate and not to direct the activities. It is anticipated that
decisions in all collaborative activities will be reached by consensus of the
KOMP2 Steering Committee, of which the PI is a member, and that the
NCRR Project Scientist will participate in this process. The NCRR Project
Scientist shall participate as a member of the Steering Committee and will have
one vote.

The Project Scientist will:

Participate
(with the P.I. and the other Steering Committee members) in the group process
of setting research priorities for the KOMP2 Research Network,
deciding optimal research approaches and protocol designs, and contributing to
the adjustment of research protocols or approaches as warranted. The Project
Scientist will assist and facilitate the group process and not direct it;

Negotiate
goals for throughput, quality, and cost with the awardee, as necessary;

Serve
as a liaison between the awardee and the Panel of Scientific Consultants, the
National Advisory Research Resources Council, the National Advisory Council for
Human Genome Research, other national advisory councils or boards;

Coordinate
the efforts of the awardee with other participants in the KOMP2 and
IMPC programs, including other awardees under this RFA, with any other
large-scale knockout efforts in the U.S., with international mouse knockout
projects, and with the larger biological research community;

Attend
all Steering Committee meetings as a voting member and assist in developing
operating guidelines, quality control procedures, and consistent policies for
dealing with recurrent situations that require coordinated action;

Periodically
report progress to the NIH Knockout Mouse Working Group, the Directors of NCRR,
NHGRI, DPCPSI and the Directors of the NIH Institutes supporting the KOMP2;

Lend
relevant expertise and overall knowledge of NIH-sponsored research to
facilitate the selection of scientists not affiliated with the awardee institutions
who are to serve on the Panel of Scientific Consultants and the Steering
Committee;

Serve
as liaison between the Steering Committee and the Panel of Scientific
Consultants;

Serve
on subcommittees of the Steering Committee, as appropriate; to provide advice
in the management and technical performance of the investigation;

Assist
in promoting the availability of the mouse knockout mutants and related
materials and resources developed in the course of this project to the
scientific research community-at large;

Participate
in data analyses, interpretations, and where warranted, authoring of the
publication of results of studies conducted as part of the KOMP2 Research Network;

Assist
awardees in the development, if needed, of policies for dealing with situations
that require coordinated action;

Retain
the option to recommend, with the advice of the Panel of Scientific
Consultants, the withholding or reduction of support from any cooperative
agreement that substantially fails to achieve its goals according to the
milestones agreed to at the time of award, or fails to maintain the state of
the art in the production of mouse knockout mutants or fails to comply with the
Terms and Conditions of the award. An NCRR Program Director will be responsible
for the normal stewardship of this award; this same Program Director may, in
addition, be substantially involved as the NIH Project Scientist, as described
above.

Conduct
an interim administrative review of the entire KOMP2 in the 3rd or
4th year to assess whether the program is accomplishing its goal as a pilot to
set the stage for an additional 5 year program to scale up in order to
phenotype all the IKMC knockout mutants. This will be done in collaboration
with the PSC.

Additionally,
an agency program official or IC program director will be responsible for the
normal scientific and programmatic stewardship of the award and will be named
in the award notice. The assigned program director may also serve as an NIH
Project Scientist.

2.A.3.
Collaborative Responsibilities

The KOMP2 Research Network will involve three distinct activities (generation of the
knockout mouse resource, a data coordination center, and KOMP2 phenotyping centers); funding of these activities will be solicited by a set of
set of three RFAs (RM-10-013 (the current RFA), RFA-RM-10-012, RFA-RM-10-011). All components of the KOMP2 program will be funded by cooperative agreements and a single Steering
Committee (section 2.A.3) and a single Panel of Scientific Consultants (section
2.A.4) will serve for all of the KOMP2 activities. The Terms and
Conditions described below are specific for this RFA (RM-10-013), but have been
coordinated and made consistent with those described in the other FOAs
soliciting components of the KOMP2 Research Network.

The Steering Committee will
serve as the main governing board of the KOMP2 Research Network. The
Steering Committee membership will include the P.I. of each awarded cooperative
agreement and the NIH Project Scientist of each of the components of the KOMP2 Research Network. Additional members may be added by action of the Steering
Committee. Members of the KOMP2 Working Group may attend the
Steering Committee meetings. Government employees outside of KOMP2 Working Group members may also attend, if their expertise is required for
specific discussions.

The Steering Committee will:

Discuss
progress in meeting the goals of the KOMP2 to provide a
comprehensive collection of phenotyped null mutant mice to the research
community;

Discuss
potential modifications of the goals of the KOMP2 in light of
developing technology and any changes in the scientific community's need for
phenotyped mouse knockout mutants;

Develop
recommendations for uniform procedures and policies necessary to meet the goals
of the KOMP2, for example for data quality measures and assessment,
nomenclature and annotation conventions for data deposition, for the KOMP2 Research Network. Adoption of procedures and policies developed by the Steering
Committee will require concurrence by the KOMP2 Working Group and
the Panel of Scientific Consultants;

Serve
as a venue for coordination on the improvement of mouse knockout phenotype
production, for example by reporting progress, disseminating best practices and
collectively evaluating new procedures, resources, and technologies.

Interact
as an active member with the IMPC

Each full member will have
one vote; the total votes of the NIH Project Scientist-members of the Steering
Committee will constitute a minority of the votes. Awardee members of the
Steering Committee will be required to accept and implement policies approved
by the Steering Committee.

Panel of Scientific
Consultants:

This program will be
coordinated with and be a member of the IMPC. Because that program is in its
formative stage, the degree of interactions of the KOMP2 Steering
committee with the IMPC and the nature of IMPC input into the oversight of the
KOMP2 is not yet known. The advisory structure may
include:

A Panel of Scientific
Consultants (PSC) will be responsible for reviewing and evaluating the progress
of the members of the KOMP2 Research Network toward meeting their
individual and collective goals. The PSC will provide recommendations to the
KOMP2 Working Group, the Directors of NHGRI, NCRR, and DPCPSI as
well as the Directors of the all other participating institutes, about
continued support of the components of the KOMP2 Research Network.
The Panel will be composed of four to six senior scientists with relevant
expertise who are not P.I.s of a cooperative agreement involved in the KOMP2 Research Network. The Panel of Scientific Consultants will be appointed by the
Directors of NHGRI, NCRR, and DPCPSI with concurrence from the Directors of all
other participating Institutes. The membership of the Panel of Scientific
Consultants may be enlarged permanently, or on an ad hoc basis, as needed.

The Panel of Scientific
Consultants will meet at least once a year and by conference call 2 to 3 times
per year. During part of this meeting, there will be a joint meeting with the
Steering Committee to allow the PSC members to interact directly with the
awardees. Annually, the PSC will make recommendations to the NIH regarding
progress of the KOMP2 Research Network and present advice about
changes, if any, which may be necessary in the KOMP2 Research
Network program to the Directors of NHGRI, NCRR and DPCPSI and the Directors of
the other participating institutes.

The KOMP2 Working
Group consists of program staff from the each of the NIH institutes supporting
the KOMP2. The purpose of the KOMP2 Working Group will be
to disseminate information about the progress of the KOMP2 Research
Network to the participating institutes and to provide a forum for the
participating institutes to discuss issues related to KOMP2. The
KOMP2 Working Group members will report to the Director of their
respective IC. The KOMP2 Working Group will be chaired by the NHGRI
Project Scientist for the knockout mouse phenotyping component of the KOMP2.

2.A.4.
Dispute Resolution Process

Any disagreements that
may arise in scientific or programmatic matters (within the scope of the award)
between award recipients and the NIH may be brought to Dispute Resolution. A
Dispute Resolution Panel composed of three members will be convened. It will
have three members: a designee of the Steering Committee chosen without NIH
staff voting, one NIH designee, and a third designee with expertise in the
relevant area who is chosen by the other two; in the case of individual
disagreement, the first member may be chosen by the individual awardee. This
special dispute resolution procedure does not alter the awardee's right to
appeal an adverse action that is otherwise appealable in accordance with PHS
regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

Each awardee will be asked
to define a set of monthly milestones at the time of the award and to update
these milestones annually at the anniversary date. These will be made a
condition of the award. In accord with the procedures described above, NCRR may
withhold or reduce funds for a project that substantially fails to meet its
milestones or to maintain the state of the art in the field.

A
final progress report, invention statement, and Financial Status Report are
required when an award is relinquished when a recipient changes institutions or
when an award is terminated.

Section
VII. Agency Contacts

We
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research, peer review, and financial or grants
management issues:

Human
Subjects Protection:Federal regulations
(45CFR46) require that applications and proposals involving human subjects must
be evaluated with reference to the risks to the subjects, the adequacy of
protection against these risks, the potential benefits of the research to the
subjects and others, and the importance of the knowledge gained or to be gained
(http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and
Safety Monitoring Plan:Data and safety
monitoring is required for all types of clinical trials, including physiologic
toxicity and dose-finding studies (phase I); efficacy studies (Phase II);
efficacy, effectiveness and comparative trials (Phase III). Monitoring should
be commensurate with risk. The establishment of data and safety monitoring
boards (DSMBs) is required for multi-site clinical trials involving
interventions that entail potential risks to the participants (NIH Policy for
Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing
Research Data:Investigators
submitting an NIH application seeking $500,000 or more in direct costs in any
single year are expected to include a plan for data sharing or state why this
is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators
should seek guidance from their institutions, on issues related to
institutional policies and local IRB rules, as well as local, State and Federal
laws and regulations, including the Privacy Rule.

Policy
for Genome-Wide Association Studies (GWAS):NIH is interested in advancing genome-wide association
studies (GWAS) to identify common genetic factors that influence health and
disease through a centralized GWAS data repository. For the purposes of this
policy, a genome-wide association study is defined as any study of genetic variation
across the entire human genome that is designed to identify genetic
associations with observable traits (such as blood pressure or weight), or the
presence or absence of a disease or condition. All applications, regardless of
the amount requested, proposing a genome-wide association study are expected to
provide a plan for submission of GWAS data to the NIH-designated GWAS data
repository, or provide an appropriate explanation why submission to the
repository is not possible. Data repository management (submission and access)
is governed by the Policy for Sharing of Data Obtained in NIH Supported or
Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088.
For additional information, see http://grants.nih.gov/grants/gwas/.

Access
to Research Data through the Freedom of Information Act:The Office of
Management and Budget (OMB) Circular A-110 has been revised to provide access
to research data through the Freedom of Information Act (FOIA) under some
circumstances. Data that are (1) first produced in a project that is supported
in whole or in part with Federal funds and (2) cited publicly and officially by
a Federal agency in support of an action that has the force and effect of law
(i.e., a regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has provided
guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Sharing of Model
Organisms:NIH is committed to
support efforts that encourage sharing of important research resources
including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to
elect and retain title to subject inventions developed with Federal funding
pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm).
All investigators submitting an NIH application or contract proposal, beginning
with the October 1, 2004 receipt date, are expected to include in the
application/proposal a description of a specific plan for sharing and
distributing unique model organism research resources generated using NIH
funding or state why such sharing is restricted or not possible. This will
permit other researchers to benefit from the resources developed with public
funding. The inclusion of a model organism sharing plan is not subject to a
cost threshold in any year and is expected to be included in all applications
where the development of model organisms is anticipated.

Inclusion of Women
And Minorities in Clinical Research:It is the policy of the
NIH that women and members of minority groups and their sub-populations must be
included in all NIH-supported clinical research projects unless a clear and
compelling justification is provided indicating that inclusion is inappropriate
with respect to the health of the subjects or the purpose of the research. This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43). All investigators proposing clinical research should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of
Children as Participants in Clinical Research:The NIH maintains a
policy that children (i.e., individuals under the age of 21) must be included
in all clinical research, conducted or supported by the NIH, unless there are
scientific and ethical reasons not to include them.

Required Education
on the Protection of Human Subject Participants:NIH policy requires
education on the protection of human subject participants for all investigators
submitting NIH applications for research involving human subjects and
individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

NIH Public Access
Policy Requirement:In
accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html)
investigators must submit or have submitted for them their final, peer-reviewed
manuscripts that arise from NIH funds and are accepted for publication as of
April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly
available no later than 12 months after publication. As of May 27, 2008,
investigators must include the PubMed Central reference number when citing an
article in NIH applications, proposals, and progress reports that fall under
the policy, and was authored or co-authored by the investigator or arose from
the investigator’s NIH award. For more information, see the Public
Access webpage at http://publicaccess.nih.gov/.

Standards
for Privacy of Individually Identifiable Health Information:The Department
of Health and Human Services (DHHS) issued final modification to the
"Standards for Privacy of Individually Identifiable Health
Information", the "Privacy Rule", on August 14, 2002. The
Privacy Rule is a federal regulation under the Health Insurance Portability and
Accountability Act (HIPAA) of 1996 that governs the protection of individually
identifiable health information, and is administered and enforced by the DHHS
Office for Civil Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and
research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH
Grant Applications or Appendices:
All
applications and proposals for NIH funding must be self-contained within
specified page limitations. For publications listed in the appendix and/or
Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide
any other information necessary for the review because reviewers are
under no obligation to view the Internet sites. Furthermore, we caution
reviewers that their anonymity may be compromised when they directly access an
Internet site.

Healthy
People 2010:The Public
Health Service (PHS) is committed to achieving the health promotion and disease
prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This FOA is related to one or more of the
priority areas. Potential applicants may obtain a copy of "Healthy People
2010" at http://www.health.gov/healthypeople.

Authority and
Regulations:This
program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive
Order 12372. Awards are made under the authorization of Sections 301 and 405 of
the Public Health Service Act as amended (42 USC 241 and 284) and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the
terms and conditions, cost principles, and other considerations described in
the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly
encourages all grant recipients to provide a smoke-free workplace and
discourage the use of all tobacco products. In addition, Public Law 103-227,
the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in
some cases, any portion of a facility) in which regular or routine education,
library, day care, health care, or early childhood development services are
provided to children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

Loan
Repayment Programs:NIH encourages
applications for educational loan repayment from qualified health professionals
who have made a commitment to pursue a research career involving clinical,
pediatric, contraception, infertility, and health disparities related areas.
The LRP is an important component of NIH's efforts to recruit and retain the
next generation of researchers by providing the means for developing a research
career unfettered by the burden of student loan debt. Note that an NIH grant is
not required for eligibility and concurrent career award and LRP applications
are encouraged. The periods of career award and LRP award may overlap providing
the LRP recipient with the required commitment of time and effort, as LRP
awardees must commit at least 50% of their time (at least 20 hours per week
based on a 40 hour week) for two years to the research. For further
information, please see: http://www.lrp.nih.gov.